Razaxaban Hydrochloride

Conventional prothrombin time (PT) assays have limited sensitivity and dynamic range in monitoring the anticoagulant activity of direct factor Xa inhibitors. Hence, new assays are needed. We modified a PT assay by adding calcium chloride (CaCl2) to the thromboplastin reagent to increase assay dynamic range and improve sensitivity. Effects of calcium and sodium ion concentrations, and sample handling, were evaluated to optimize assay performance. Increasing concentrations of calcium ions produced progressive increases in PT across the factor Xa inhibitor concentrations of 0 to 2500 nmol/L for razaxaban and apixaban. The greatest effect was seen when the thromboplastin reagent was diluted 1:2.25 with 100 mmol/L CaCl2 (thus selected for routine use). The optimized assay showed an interassay precision of 1.5 to 9.3 percentage coefficient of variation (%CV) for razaxaban and 3.1 to 4.6 %CV for apixaban. We conclude that the modified PT assay is likely to be suitable as a pharmacodynamic marker for activity at therapeutic concentrations of factor Xa inhibitors.

Three model compounds were used to study the effect of process parameters on in-process critical material attributes and a final product critical quality attribute. The effect of four process parameters was evaluated using design of experiment approach. Batches were characterized for particle size distribution, density (porosity), flow, compaction, and dissolution rate. The mechanisms of the effect of process parameters on primary granule properties (size and density) were proposed. Water amount showed significant effect on granule size and density. The effect of impeller speed was dependent on the granule mechanical properties and efficiency of liquid distribution in the granulator. Blend density was found to increase rapidly during wet massing. Liquid addition rate was the least consequential factor and showed minimal impact on granule density and growth. Correlations of primary properties with granulation bulk powder properties (compaction and flow) and tablet dissolution were also identified. The effects of the process parameters on the bulk powder properties and tablet dissolution were consistent with their proposed link to primary granule properties. Understanding the impact of primary granule properties on bulk powder properties and final product critical quality attributes provides the basis for modulating granulation parameters in order to optimize product performance.